Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of protein phosphorylation in the action of anti-L on low potassium (LK) sheep red cells. Anti-L stimulated the Na/K pump by four- to fivefold, but Na/K pump activity in anti-L-stimulated or in control cells was unaffected by protein kinase/protein phosphatase (PK/PP) inhibitors. KCl co-transport activity was inhibited by anti-L (about 50%). Co-transport was stimulated by staurosporine; and inhibited by calyculin A, okadaic acid, tyrphostin B46 and genistein; with a similar pattem in both control and anti-L-treated cells. O2 sensitivity of KCl co-transport was similar in control and anti-L-treated cells. Neither control nor anti-L-stimulated Na/K pump activities were O2 sensitive. Incubation with urea stimulated KCl co-transport in both control and anti-L-treated cells. Inhibition of co-transport by anti-L was unaffected by low concentrations of urea but was reduced at higher urea concentrations. Na/K pump activity of control cells was unaffected by incubation with urea, but that in cells stimulated by anti-L was reduced, though not significantly. Under high hydrostatic pressure, KCl co-transport was stimulated, and the inhibitory effects of PP inhibition (okadaic acid), anti-L or combinations of the two were reduced. Results suggest that anti-L does not affect K+ transport in LK sheep red cells via protein phosphorylation.
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PMID:Effects of protein kinase and phosphatase inhibitors and anti-L antisera on K+ transport in LK sheep red cells. 1112 38

The gene pzl-1 from the filamentous fungus Neurospora crassa encodes a putative Ser/Thr protein phosphatase that is reminiscent of the Ppz1/Ppz2 and Pzh1 phosphatases from Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. The entire PZL-1 protein, as well as its carboxyl-terminal domain, have been expressed in Escherichia coli as active protein phosphatases. To characterize its cellular role, PZL-1 was also expressed in Sz. pombe and in S. cerevisiae. Expression of PZL-1 in S. cerevisiae from the PPZ1 promoter was able to rescue the altered sensitivity to caffeine and lithium ions of a ppz1 strain. Furthermore, high copy number expression of PZL-1 alleviated the lytic phenotype of a S. cerevisiae slt2/mpk1 mitogen-activated protein (MAP) kinase mutant, similarly to that described for PPZ1, and mimicked the effects of high levels of Ppz1 on cell growth. Expression of PZL-1 in fission yeast from a weak version of the nmt1 promoter fully rescued the growth defect of a pzh1Delta strain in high potassium, but only partially complemented the sodium-hypertolerant phenotype. Strong overexpression of the N. crassa phosphatase in Sz. pombe affected cell growth and morphology. Therefore, PZL-1 appears to fulfil every known function carried out by its S. cerevisiae counterpart, despite the marked divergence in sequence within their NH(2)-terminal moieties.
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PMID:Functional analysis of the Neurospora crassa PZL-1 protein phosphatase by expression in budding and fission yeast. 1116 54

A stable CHO-K1 cell line was developed which expresses the human small conductance calcium-activated potassium channel hSK3. Immunofluorescence microscopy using an anti-SK3 antibody and radioligand binding using [(125)I]-apamin demonstrated the presence of hSK3 channel in the recombinant cell line. This cell line was utilised in a fluorescence assay using the membrane potential-sensitive dye DiBAC(4)(3) to functionally analyse and pharmacologically characterise this potassium channel. The analysis of known blockers of calcium-activated potassium channels revealed the highest potency for apamin (IC(50)=13.2 nM). This result was confirmed by direct recordings of SK3 currents using the whole-cell patch-clamp technique. Tricyclic antidepressants such as desipramine, imipramine and nortriptyline as well as phenothiazines such as fluphenazine, promethazine, chlorpromazine and trifluoperazine blocked the hSK3 channel with micromolar potencies. These compounds also displaced [(125)I]-apamin binding to the hSK3 channel thus suggesting direct and competitive channel blocking activity. Since these compounds share a common three-ring molecular core structure, this feature seems to be important for channel blocking activity. The serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A were able to abolish channel activation with nanomolar potencies, but did not displace [(125)I]-apamin binding. Thus, phosphorylation of hSK3 or an accessory channel subunit seems to be involved in its modulation.
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PMID:Pharmacological characterisation of the human small conductance calcium-activated potassium channel hSK3 reveals sensitivity to tricyclic antidepressants and antipsychotic phenothiazines. 1136 31

The ability of intracellular parasites to monitor the viability of their host cells is essential for their survival. The protozoan parasite Toxoplasma gondii actively invades nucleated animal cells and replicates in their cytoplasm. Two to 3 days after infection, the parasite-filled host cell breaks down and the parasites leave to initiate infection of a new cell. Parasite egress from the host cell is triggered by rupture of the host plasma membrane and the ensuing reduction in the concentration of cytoplasmic potassium. The many other changes in host cell composition do not appear be used as triggers. The reduction in the host cell [K(+)] appears to activate a phospholipase C activity in Toxoplasma that, in turn, causes an increase in cytoplasmic [Ca(2+)] in the parasite. The latter appears to be necessary and sufficient for inducing egress, as buffering of cytoplasmic Ca(2+) blocks egress and calcium ionophores circumvent the need for a reduction of host cell [K(+)] and parasite phospholipase C activation. The increase in [Ca(2+)](C) brings about egress by the activation of at least two signaling pathways: the protein kinase TgCDPK1 and the calmodulin-dependent protein phosphatase calcineurin.
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PMID:The loss of cytoplasmic potassium upon host cell breakdown triggers egress of Toxoplasma gondii. 1152 13

1. Large-conductance Ca(2+)- and voltage-activated potassium (BK) channels are important regulators of cellular excitability. Here, we present a patch-clamp electrophysiological analysis of splice-variant-specific regulation by the synthetic glucocorticoid dexamethasone (DEX) of BK channels consisting of cloned STREX or ZERO alpha-subunit variants expressed in human embryonic kidney (HEK 293) cells. 2. STREX channels in isolated membrane patches were inhibited by protein kinase A (PKA) and this was blocked on pre-treatment of intact cells with DEX (100 nM) for 2 h. 3. The effect of DEX required the synthesis of new mRNA and protein. Furthermore, it required protein phosphatase 2A (PP2A)-like activity intimately associated with the channels, as it was blocked by 10 nM okadaic acid but not by the specific protein phosphatase-1 inhibitor peptide PPI-2. 4. ZERO variant channels that lack the STREX insert were activated by PKA but were not influenced by DEX. ZERO channels containing a mutant STREX domain (S4(STREX)A) were also activated by PKA. Importantly, DEX blocked PKA activation of S4(STREX)A channels in a PP2A-dependent manner. 5. Taken together, the STREX domain is crucial for glucocorticoid regulation of BK channels through a PP2A-type enzyme. Moreover, glucocorticoids appear to induce a generic set of proteins in different types of cells, the actions of which depend on the expression of cell-specific targets.
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PMID:Alternative splicing determines sensitivity of murine calcium-activated potassium channels to glucocorticoids. 1171 61

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by beta adrenergic receptor (betaAR) activation, which increases the slow outward potassium ion current (IKS). Mutations in two human I(KS) channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that betaAR modulation of I(KS) requires targeting of adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through IKS.
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PMID:Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. 1179 44

The present study was designed to assess the effect of okadaic acid (OA), a protein phosphatase inhibitor, on aldosterone secretion in response to angiotensin II (AII), adrenocorticotropin (ACTH) and rises in external potassium concentration (K+). AII (10nM) caused a 20-fold increase in aldosterone production and OA reduced this response by 45%. ACTH (10nM) caused an 8.6-fold increase in aldosterone secretion and OA reduced this by 83%. Increasing K+ concentration from 3 to 12mM caused a 13-fold increase in aldosterone production, which OA inhibited by 36%. These results suggest that protein phosphatases participate in the control of adrenal steroid production, even though ACTH, AII and K+ act via different intracellular messenger systems.
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PMID:Okadaic acid inhibits angiotensin II, adrenocorticotropin and potassium-dependent aldosterone secretion. 1194 18

Sirolimus and cyclosporine (CsA) prevent acute rejection in man when used as primary therapies in triple drug regimens. Sirolimus does not act via the calcineurin pathway and therefore is not expected to produce the same renal side-effects. This paper presents the pooled 2-year data analysis of renal function parameters from two open-label, randomized, multicenter studies. Patients (18-68 years) receiving a primary renal allograft were randomized to receive concentration-controlled sirolimus (n = 81) or CsA (n = 80), in combination with azathioprine and steroids (n = 83), or mycophenolate mofetil (MMF) and steroids (n = 78). From week 10 through year 2, calculated glomerular filtration rate (GFR) was significantly higher in sirolimus--than in CsA-treated patients (69.3 vs. 56.8 mL/min, at 2 years, p = 0.004). Serum uric acid was significantly higher in the CsA-treated patients and magnesium was significantly lower; these parameters were more likely to be within normal limits in the sirolimus group. Mean serum potassium and phosphorus were lower in sirolimus-treated patients. In conclusion, sirolimus, when administered as primary therapy in combination with azathioprine or MMF, has a favorable safety profile compared to CsA with regards to renal function.
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PMID:Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. 1212 9

Cerebellar granule neurons undergo apoptosis when switched from medium containing depolarizing levels of potassium (high K+ medium, HK) to medium containing low K+ (LK). NF-kappaB, a ubiquitously expressed transcription factor, is involved in the survival-promoting effects of HK. However, neither the expression nor the intracellular localization of the five NF-kappaB proteins, or of IkappaB-alpha and IkappaB-beta, are altered in neurons primed to undergo apoptosis by LK, suggesting that uncommon mechanisms regulate NF-kappaB activity in granule neurons. In this study, we show that p65 interacts with the transcriptional co-activator, CREB-binding protein (CBP), in healthy neurons. The decrease in NF-kappaB transcriptional activity caused by LK treatment is accompanied by a reduction in the interaction between p65 and CBP, an alteration that is accompanied by hyperphosporylation of CBP. LK-induced CBP hyperphosphorylation can be mimicked by inhibitors of protein phosphatase (PP) 2A and PP2A-like phosphatases such as okadaic acid and cantharidin, which also causes a reduction in p65-CBP association. In addition, treatment with these inhibitors induces cell death. Treatment with high concentrations of the broad-spectrum kinase inhibitor staurosporine prevents LK-mediated CBP hyperphosphorylation and inhibits cell death. In vitro kinase assays using glutathione-S-transferase (GST)-CBP fusion proteins map the LK-regulated site of phosphorylation to a region spanning residues 1662-1840 of CBP. Our results are consistent with possibility that LK-induced apoptosis is triggered by CBP hyperphosphorylation, an alteration that causes the dissociation of CBP and NF-kappaB.
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PMID:Apoptosis in cerebellar granule neurons is associated with reduced interaction between CREB-binding protein and NF-kappaB. 1255 2

The role of elongation factor (EF)-2 phosphorylation in the regulation of pancreatic beta-cell protein synthesis by glucose was investigated in the INS-1-derived cell line 832/13. Incubation of cells in media containing 1 mm glucose resulted in a progressive increase in EF-2 phosphorylation that was maximal by 1-2 h. Readdition of 10 mm glucose promoted a rapid dephosphorylation of EF-2 that was complete in 10 min and maintained over the ensuing 2 h. Similar results were obtained using primary rat islets or Min-6 insulinoma cells. The glucose effect in 832/13 cells was replicated by addition of pyruvate or alpha-ketocaproate, but not 2-deoxyglucose, suggesting that mitochondrial metabolism was required. Accordingly, glucose-mediated dephosphorylation of EF-2 was completely blocked by the mitochondrial respiratory antagonists antimycin A and oligomycin. The hyperglycemic effect was not mimicked by incubation of cells in 100 nm insulin, 30 mm potassium chloride, or 0.25 mm diazoxide, indicating that insulin secretion and/or depolarization of beta cells was not required. The locus of the high glucose effect appeared to be protein phosphatase-2A, the principal phosphatase acting on EF-2. Protein phosphatase-2A activity was stimulated by glucose addition to 832/13 cells, but neither protein phosphatase-1 nor calmodulin kinase III (EF-2 kinase) activity was affected under these conditions. The slower rephosphorylation of EF-2 during the transition from high to low glucose may involve effects on EF-2 kinase activity. Addition of 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside in high glucose led to a marked stimulation of EF-2 phosphorylation, consistent with the possibility that increased AMP kinase activity in low glucose stimulates EF-2 kinase. In parallel with the effects on EF-2 dephosphorylation, addition of high glucose to 832/13 cells markedly increased the incorporation of [(35)S]methionine into total protein. Taken together, these results suggest that modulation of extracellular glucose impacts protein translation rate in beta cells at least in part through regulation of the elongation step, via phosphorylation/dephosphorylation of EF-2.
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PMID:Glucose regulates EF-2 phosphorylation and protein translation by a protein phosphatase-2A-dependent mechanism in INS-1-derived 832/13 cells. 1264 53


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